This invention relates to improved liposomal camptothecin compositions and methods of manufacturing and using such compositions for treating neoplasia and for inhibiting angiogenesis.
Therapeutic camptothecins, such as Topotecan (9-dimethylaminomethyl-10-hydroxy-camptothecin; Hycamtin™), and Irinotecan, are a semi-synthetic, water soluble derivative of camptothecin, an alkaloid extracted from the stem wood of the Chinese tree Camptotheca acuminata (Wall, et al., J. Am. Chem. Soc. 88:3888–3890 (1966)). Camptothecins belong to the topoisomerase inhibitor class of antineoplastic agents, specifically inhibiting the action of the nuclear enzyme topoisomerase I which is involved in DNA replication (Hsiang, et al., Cancer Res. 48:1722–1726 (1988)). As such, topotecan exhibits a cell cycle-specific mechanism of action, acting during S-phase (DNA replication) to cause irreversible double strand breaks in DNA that ultimately lead to G2 cell cycle arrest and apoptosis. In the free form, the drug has a broad spectrum of activity against a range of tumor cell lines and murine allograft and human xenograft tumor models (McCabe, F. L. et al, Cancer Invest 12:308–313 (1994); Emerson, et al, Cancer Res. 55:603–609 (1995); Thompson, Biochim. Biophys. Acta 1400:301–319 (1998); Ormrod, et al., Drugs 58:533–551 (1999); Hardman, et al., Anticancer Res. 19:2269–2274 (1999)). More recently, evidence has emerged that topotecan has strong anti-angiogenic properties that may contribute to its anti-tumor mechanism of action (O'Leary, et al., Clin. Cancer Res. 5:181–187 (1999); Clements, et al., Cancer Chemother. Pharmacol. 44:411–416 (1999)). All these treatments are associated with dose-limiting toxicity such as non-cumulative myelosuppression leading to anaemia, neutropenia and thrombocytopenia, and gastrointestinal-related toxicity, including mucositis and diarrhea. Clinically, topotecan has been approved for second-line therapy in ovarian and small cell lung cancer (SCLC) and is currently the focus of extensive clinical evaluation.
Lipid formulations of camptothecins have been proposed as therapeutic agents (see, U.S. Pat. No. 5,552,156 and PCT Publication No. WO 95/08986. However, not all lipid formulations are equal for drug delivery purposes and extensive research continues into formulations which demonstrate preferred characteristics for drug loading and storage, drug administration, pharmacokinetics, biodistribution, leakage rates, tumor accumulation, toxicity profile, and the like. With camptothecins, the field is further complicated because dose limiting toxicities in humans may be 10-fold lower than in mice (Erickson-Miller, et al., Cancer Chemother. Pharmacol. 39:467–472 (1997)).
In short, camptothecins are a promising class of anti-neoplastic agents, and lipid formulations of these drugs could prove very useful. However, to date, lipid formulations have not provided sufficiently remarkable activity to warrant clinical advancement. It is an object of the instant invention to provide novel lipid formulated camptothecins having novel clinical utility.